A continuous noninvasive bedside monitor of cerebral blood flow (CBF) will be useful for diagnosis and management of any brain injury or disease associated with ischemia or inadequate vascular autoregulation. Continuous CBF monitoring during surgery or in any intensive care setting will help with patient management to improve cerebral outcomes. Near-infrared spectroscopy (NIRS) can measure hemoglobin concentration (HbT) and oxygenation (SO2) but without measuring cerebral perfusion can only partially assess cerebral hemodynamics. Diffuse correlation spectroscopy (DCS) is an emerging optical modality to monitor CBF continuously and noninvasively using near-infrared continuous light. DCS measures an index of blood flow (CBFi) by quantifying the temporal fluctuations of light generated by the dynamic scattering of moving red blood cells. Following recent positive results with several clinical applications, obtained by us and several other groups, more and more researchers are starting to adopt DCS technology. As with NIRS, extra-cerebral layers contaminate DCS cerebral blood flow estimates and, to correctly quantify absolute CBFi values, knowledge of the optical properties of the investigated tissue are needed. For this R21, we propose to develop a completely brand new technique, time-domain DCS (TD-DCS), by employing novel long coherence pulsed lasers and detecting both photon arrival times in each pulse and time-gated autocorrelation decay across pulses. By operating DCS in time-domain instead of continuous-wave (CW) mode, we will be able to exploit the many advantages of time-resolved reflectance spectroscopy (TRS). As shown by our Monte Carlo simulations, by evaluating the autocorrelation function over different time gates, with TD-DCS we will be able to differentiate between short and long photon paths through the tissue and achieve higher sensitivity to the brain than by using CW illumination. Further, this high sensitivity to the brain can be achieved at shorter source-detector separations, allowing for a higher number of detected photons. In addition TRS analysis will allow us to evaluate cerebral optical properties and improve the reliability of absolute CBFi comparisons between subjects. Time-tagging photon arrivals will enable multiple analyses from the same data stream allowing for the first time, simultaneous quantification of HbT, SO2, and CBF within a single measurement. With this proposal we will build the first TD-DCS prototype and develop synergistic TD and DCS methods and analysis procedures to achieve superior performances while retaining cost effectiveness. We will evaluate the optimal operation parameters and characterize and test the prototype in phantoms. Finally, we will demonstrate system performance in human subjects. This initial feasibility study will provide motivation for larger studies. This method has the potential to overcome the limitations of present cerebral hemodynamic oximetry methods.